4-amino-4-ene-steroids and their use as 5α-reductase inhibitors

Abstract

The present invention relates to 4-amino-Δ 4 -steroids which are useful as inhibitors of 5α-reductase. The compounds are prepared by the reaction of an appropriate 4-azido steroid with triphenylphosphine in an aqueous inert solvent with heating. The present application is a continuation-in-part of application Ser. No. 561,041, filed Aug. 1, 1990 and application Ser. No. 671,555, filed Mar. 19, 1991.

What is claimed is: 
     
       1. A compound of the formula: ##STR9## wherein R is hydrogen or C 1-4  alkyl; R 1  is C 2-6  alkanoyl, --(C 1-6  alkyl)-OZ 2 , --(C 2-6  alkyl)--(OZ 2 ) 2  or --A--C(O)--Y; Z 2  is hydrogen, C 1-6  alkyl, phenyl-(C 1-4  alkyl), (Y 1  -substituted phenyl)-(C 1-4  alkyl), C 1-6  alkanoyl, benzoyl or Y 1  -substituted benzoyl wherein Y 1  is methyl, halogen or methoxy; A is absent or is present as an alkylene of 1 to 6 carbon atoms; Y is --OH, --O(C 1-6  alkyl) or --NR 3  R 4  ; R 2  is hydrogen or R 1  and R 2  can be combined to give --O--CH 2  CH 2  CH 2  ---; R 3  and R 4  are each independently hydrogen, C 1-6  alkyl, C 3-6  cycloalkyl or they can be combined to give --(CH 2 ) n  --wherein n is 4 to 6; R 5  is hydrogen or methyl; X is O or (H)(H); Z is hydrogen or C 1-6  alkyl; Z 1  is hydrogen or methylene; and each of the dotted lines in the rings indicates the optional presence of a double bond with the proviso that a 9,11-double bond can only be present when X is (H)(H) and the proviso that, when a 16,17-double bond is present, then R 2  is absent. 
     
     
       2. A compound according to claim 1 which has the formula: ##STR10## wherein R is hydrogen or C 1-4  alkyl; R 1  is C 2-6  alkanoyl, --CH(CH 3 )--CH 2  OZ 2 , --CH(CH 3 )--COO(C 1-6  alkyl) or --C(O)--NR 3  R 4  ; R 2  is hydrogen or R 1  and R 2  can be combined to give --O--CH 2  CH 2  CH 2  ---; Z 2  is hydrogen, C 1-6  -alkyl or C 1-6  alkanoyl; R 3  and R 4  are each independently hydrogen, C 1-6  alkyl, C 3-6  cycloalkyl or they can be combined to give --(CH 2 ) n  --wherein n is 4 to 6. 
     
     
       3. A compound according to claim 2 which has the formula: ##STR11## wherein R is hydrogen or C 1-4  alkyl; R 3  and R 4  are each independently hydrogen, C 1-6  alkyl, C 3-6  cycloalkyl or they can be combined to give --(CH 2 ) n  --wherein n is 4 to 6. 
     
     
       4. A compound according to claim 3 which has the formula: ##STR12## wherein R 3  and R 4  are each independently hydrogen or C 1-6  alkyl 
     
     
       5. A compound according to claim 4 which is 4-amino-N-(1,1-dimethylethyl)-3-oxoandrost-4-ene-17β-carboxamide 
     
     
       6. A compound according to claim 4 which is 4-amino-N,N-bis(1-methylethyl)-3-oxoandrost-4-ene-17β-carboxamide. 
     
     
       7. A compound according to claim 1 which has the formula: ##STR13## wherein R is hydrogen or C 1-4  alkyl; R 1  is --(C 1-6  alkyl)-OZ 2  or --(C 2-6  alkyl)--(OZ 2 ) 2  ; Z 2  is hydrogen, C 1-6  alkyl, phenyl-(C 1-4  alkyl), (Y 1  -substituted phenyl)-(C 1-4  alkyl), C 1-6  alkanoyl, benzoyl or Y 1  -substituted benzoyl wherein Y 1  is methyl, halogen or methoxy; R 5  is hydrogen or methyl; X is O or (H)(H); Z is hydrogen or C 1-6  alkyl; Z 1  is hydrogen or methylene; and each of the dotted lines in the rings indicates the optional presence of a double bond with the proviso that a 9,11-double bond can only be present when X is (H)(H). 
     
     
       8. A compound according to claim 7 which has the formula: ##STR14## wherein Z 2  is hydrogen, C 1-6  alkyl, phenyl-(C 1-4  alkyl), (Y 1  -substituted phenyl)-(C 1-4  alkyl), C 1-6  alkanoyl, benzoyl or Y 1  -substituted benzoyl wherein Y 1  is methyl, halogen or methoxy; R 5  is hydrogen Or methyl; Z is hydrogen or C 1-6  alkyl; Z 1  is hydrogen or methylene; and each of the dotted lines in the rings indicates the optional presence of a double bond. 
     
     
       9. A compound according to claim 7 which is (20S)-4-amino-21-hydroxy-20-methylpregn-4-en-3-one.